Notch信号通路在B细胞恶性肿瘤中的研究进展

 Notch信号通路是一个进化高度保守的经典信号通路,通过调节细胞的增殖、分化和凋亡而影响细胞的命运。研究表明Notch信号的异常与多种肿瘤的发生发展有关,其在B细胞恶性肿瘤中的作用为双向调节作用,既表现为致瘤的作用,又能抑制肿瘤的发生,同时提示Notch信号可能成为B细胞恶性肿瘤治疗的新靶点。     

c-Met在肺癌中的研究进展

c-Met是酪氨酸激酶受体的一种,由MET基因编码产生.肝细胞生长因子(HGF)作为c-Met唯一的天然配体,与其结合后激活相关下游通路如PI3K、MAPK和STAT 3等,参与肿瘤的增殖、迁移、侵袭等方面.c-Met主要激活形式包括有配体依赖的自分泌或旁分泌机制和非配体依赖机制等,许多恶性肿瘤包括肺癌在内均存在c-M...     

Hedgehog信号通路在前列腺癌中的研究进展

Hedgehog信号通路与哺乳动物的胚胎发育、组织发生以及肿瘤形成等有着密切的关系,在机体发育过程中调节细胞的增殖与分化.研究证实其在晚期前列腺癌中起着重要作用.在前列腺肿瘤异种移植动物模型中,将Hedgehog信号通路阻断后可以使瘤体变小.因此,靶向抑制Hedgehog信号通路可能对前列腺癌的治疗非常有效.     

Hippo信号通路在肺癌中的研究进展

肺癌是全世界范围内肿瘤相关性死亡的首要原因,每年死亡人数超过100万人,占全球癌症死亡人数的五分之一.虽然目前在手术、放化疗、靶向治疗、免疫治疗肺癌方面取得了一定进展,但患者的预后仍不理想.因此,亟待寻找评价预后的分子标志物和肺癌的治疗新靶点,为肺癌患者提供生存获益的有效方法.近年来,Hippo信号通路逐渐成为国内外肿瘤研究领域中新兴且热门的研究方向.Hippo信号通路激活时,其核心组件MST/MOB、LATS 1/2等能抑制转录的共激活剂YAP/TAZ的转录,二者被磷酸化并滞留在细胞浆中,从而抑制肺癌的发生发展.因此Hippo信号通路在临床应用中的潜在价值也越来越受关注.本篇文章总结了Hippo信号通路核心组成元件及上下游调控因子在肺癌形成进展过程中的重要作用和分子机制,并对Hippo信号通路的研究前景进行展望.     

Hedgehog-Gli信号通路在肺癌中的研究进展

Hedgehog-Gli信号通路参与脊椎动物的胚胎发育、组织分化、器官形成,并且在稳定机体内环境、维持干细胞功能、调节上皮-间质转化中起重要作用。Hedgehog-Gli信号通路的激活与多种肿瘤的发生发展、侵袭、凋亡及耐药密切相关。本文旨在阐明Hedgehog-Gli信号通路的组成,作用机制,在肺癌发生发展过程中的作用以及在EGFR-TKI治疗EGFR突变NSCLC耐药后的作用。     

Hedgehog信号通路在胰腺癌中的研究进展

Hedgehog(HH)信号通路是一个信号级联放大反应,对大多数动物胚胎的正常发育至关重要,在成人组织中的异常激活能导致肿瘤的发生.研究发现,HH信号通路与胰腺胚胎发育密切相关,其传导异常可导致胰腺癌的发生.探讨HH信号通路在胰腺癌中的作用将为研究胰腺癌的发病机制和治疗方法提供新的思路.     

Hedgehog信号通路在胃癌中的研究进展

Hedgehog信号通路是来自内胚层的信号分子之一,在个体胚胎发育诱导、模式的形成和细胞命运的决定中起着关键的作用,信号紊乱会导致各种组织器官畸形.在个体发育成熟后,Hedgehog信号通路只在特定的部位表达,与器官正常功能的维持、机体内环境的稳定有着密切的关系.然而,越来越多的研究显示Hedgehog信号通路与肿瘤的发生发展有着密切的关联.已有研究报道胃癌中也明显存在Hedgehog信号通路的异常活化.本文从Hedgehog信号通路过度表达的机制、成员突变、非经典Hedgehog信号通路、胃癌干细胞、上皮间质转化等方面出发,将近几年来Hedgehog信号通路与胃癌发生发展关联方面的研究进展进行报道.     

JAK-STAT信号通路在卵巢癌中的研究进展

 近年来,JAK-STAT信号转导途径日渐成为研究的热点。JAK和STAT是细胞内和受体相结合的蛋白质,完成从胞质到核内的信号转导。由于该途径直接参与卵巢癌的发生及进展,采取适当方法干预甚至阻断该途径能不同程度抑制肿瘤增殖并促进其凋亡。     

Driver gene alterations and activated signaling pathways toward malignant progression of gastrointestinal stromal tumors

Mutually exclusive KIT and PDGFRA mutations are considered to be the earliest events in gastrointestinal stromal tumors (GIST), but insufficient for their malignant progression. Herein, we aimed to identify driver genes and signaling pathways relevant to GIST progression. We investigated genetic profiles of 707 driver genes, including mutations, gene fusions, copy number gain or loss, and gene expression for 65 clinical specimens of surgically dissected GIST, consisting of six metastatic tumors and 59 primary tumors from stomach, small intestine, rectum, and esophagus. Genetic alterations included oncogenic mutations and amplification‐dependent expression enhancement for oncogenes (OG), and loss of heterozygosity (LOH) and expression reduction for tumor suppressor genes (TSG). We assigned activated OG and inactivated TSG to 27 signaling pathways, the activation of which was compared between malignant GIST (metastasis and high‐risk GIST) and less malignant GIST (low‐ and very low‐risk GIST). Integrative molecular profiling indicated that a greater incidence of genetic alterations of driver genes was detected in malignant GIST (96%, 22 of 23) than in less malignant GIST (73%, 24 of 33). Malignant GIST samples groups showed mutations, LOH, and aberrant expression dominantly in driver genes associated with signaling pathways of PI3K (PIK3CA, AKT1, and PTEN) and the cell cycle (RB1, CDK4, and CDKN1B). Additionally, we identified potential PI3K‐related genes, the expression of which was upregulated (SNAI1 and TPX2) or downregulated (BANK1) in malignant GIST. Based on our observations, we propose that inhibition of PI3K pathway signals might potentially be an effective therapeutic strategy against malignant progression of GIST.     

血液系统恶性肿瘤研究进展

美国血液学会(ASH)年会是全球最具影响力的血液学会议,会议报道的研究成果体现了当今血液病从基础研究到临床实践,从诊断到治疗的最新进展.第59届ASH年会内容涵盖了从急性髓系白血病标准治疗的改进到侵袭性B细胞淋巴瘤的治疗策略,从骨髓增生异常综合征的治疗前景到生物学特性对惰性淋巴瘤治疗决策的影响,从慢性淋巴细胞白血病的个体化治疗到获得性/遗传性骨髓衰竭的研究等课题.中国学者近年来也取得了出色的研究成果,获得了国际同行的好评.     

Therapeutic targeting of multiple signaling pathways in malignant pleural mesothelioma

The majority of malignant pleural mesotheliomas (MPMs) aberrantly express the epidermal growth factor receptor (ErbB1). We examined the efficacy of GW572016 (lapatinib), a dual inhibitor of ErbB1/ErbB2 with a panel of 10 MPM cell lines. Two of the 10 MPM cell lines, H2373 and H2452, underwent G1/S cell cycle arrest and growth inhibition with an IC(50) of 1 muM and 0.8 muM, respectively. There was no relationship between the presence or the amount of ErbB1, phospho-ErbB1, phospho-ErbB2, ErbB3, ErbB4, phospho-Akt, and Akt or the ability of lapatinib to inhibit phospho-ErbB1 in these cell lines compared to those that did not respond to lapatinib. The sensitive cell lines had a time-dependent decrease in phospho-Akt and/or ERK1/2, and an increase in p27 and when treated with lapatinib. The combination of lapatinib with U0126, LY294002 or rapamycin caused greater growth inhibition than either drug alone in the sensitive cell lines while this did not occur in the resistant cell lines. Our findings suggest that ErbB1 alone is a therapeutic target for the minority of mesotheliomas and that combining ErbB1 inhibitors with signal transduction inhibitors in mesothelioma will enhance their effectiveness. Furthermore, combinations of growth factor and signal transduction inhibitors may be needed to inhibit the growth of the majority of MPM cell lines, and therefore patients with MPM.     

Pim-1在肿瘤及相关信号通路中的作用

原癌基因蛋白质c-pim-1(Pim-1)在肿瘤组织中常表达增高且与肿瘤分期、预后密切相关.研究表明,Pim-1不仅参与调控细胞增殖和凋亡,在肿瘤转移过程中也发挥重要作用.多个信号传导通路可以调控Pim-1表达与活化,同时Pim-1也可影响通路中多个重要因子,其在肿瘤发生发展中作用十分广泛,已成为肿瘤治疗的潜在靶点.     

Romidepsin targets multiple survival signaling pathways in malignant T cells

Romidepsin is a cyclic molecule that inhibits histone deacetylases. It is Food and Drug Administration-approved for treatment of cutaneous and peripheral T-cell lymphoma, but its precise mechanism of action against malignant T cells is unknown. To better understand the biological effects of romidepsin in these cells, we exposed PEER and SUPT1 T-cell lines, and a primary sample from T-cell lymphoma patient (Patient J) to romidepsin. We then examined the consequences in some key oncogenic signaling pathways. Romidepsin displayed IC₅₀ values of 10.8, 7.9 and 7.0 nm in PEER, SUPT1 and Patient J cells, respectively. Strong inhibition of histone deacetylases and demethylases, increased production of reactive oxygen species and decreased mitochondrial membrane potential were observed, which may contribute to the observed DNA-damage response and apoptosis. The stress-activated protein kinase/c-Jun N-terminal kinase signaling pathway and unfolded protein response in the endoplasmic reticulum were activated, whereas the phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin (PI3K/AKT/mTOR) and β-catenin pro-survival pathways were inhibited. The decreased level of β-catenin correlated with the upregulation of its inhibitor SFRP1 through romidepsin-mediated hypomethylation of its gene promoter. Our results provide new insights into how romidepsin invokes malignant T-cell killing, show evidence of its associated DNA hypomethylating activity and offer a rationale for the development of romidepsin-containing combination therapies.     

胆道恶性肿瘤的免疫治疗进展

胆道恶性肿瘤是一种恶性程度高、预后极差的消化系统肿瘤.目前化疗是晚期胆道恶性肿瘤的标准一线治疗,但是其治疗效果并不令人满意.近年来免疫治疗发展迅速,特别是免疫检查点抑制剂的推出,在很多实体肿瘤中均取得了良好的疗效.目前胆道系统恶性肿瘤的一些Ⅰ、Ⅱ期临床研究也展现了免疫治疗较好的安全性和有效性.本文就近年来胆道恶性肿瘤方...     

经典Wnt信号通路在恶性淋巴瘤中的研究进展

Wnt信号通路是调控机体胚胎及器官发育的重要信号通路之一,在细胞增殖、分化、极化、黏附和运动等生理过程中发挥重要作用;许多肿瘤的发病涉及经典Wnt通路的异常持续性激活。近年来,在恶性淋巴瘤发病研究中有许多涉及Wnt信号通路的激活。本文就经典Wnt信号通路在淋巴细胞发育和恶性淋巴瘤发病中的研究进展进行简要综述,旨在进一步探索淋巴瘤的发病机制,揭示基于该通路的潜在靶向治疗的可能。     

EphB6受体在恶性肿瘤中的研究进展

受体酪氨酸激酶(RTKs)是一种主要的膜受体,调控细胞增殖、分化和迁移。解除RTK信号通路的管制会导致许多疾病,如癌症和发育障碍。促红细胞生成素肝细胞受体(Erythropoietin-producing hepatocellular,Eph)家族是酪氨酸激酶受体家族中最大的一个亚族,其与配体Ephrin的相互作用在生长发育和肿瘤发生过程中发挥着重要作用。研究表明,一种缺乏酪氨酸激酶活性的特殊Eph受体EphB6在乳腺癌、结直肠癌等许多恶性肿瘤中表达下降,而大量证据表明EphB6表达的缺失依赖于其启动子DNA的高甲基化,进而促进肿瘤的进展与转移。EphB6是近期研究的热点因子,本文就其目前在恶性肿瘤中研究进展做一综述。     

二甲双胍在恶性肿瘤放疗中的应用研究进展

二甲双胍(C4H11N5)是治疗2型糖尿病的主要药物.有研究显示,二甲双胍可以抑制肿瘤生长,改善恶性肿瘤患者的预后.近年越来越多的研究发现,二甲双胍可以改善肿瘤细胞的放疗敏感性.然而,二甲双胍增强恶性肿瘤放疗敏感性的具体机制尚未完全阐明.本研究将对有关二甲双胍联合放疗应用的最新发现进行综述,并着重介绍其在不同肿瘤中的疗...     

DLL4蛋白在恶性肿瘤中的研究进展

诱导血管的生成能力是恶性肿瘤能生长、浸润与转移的前提之一。DLL4(delta-like ligand 4)配体蛋白是其上游血管内皮生长因子(VEGF)信号的Notch通路组成成分,特异性参与肿瘤血管的发生及生长的调控。近年来许多研究发现,DLL4蛋白在多种实体肿瘤血管内皮细胞中的表达显著升高。而且与肿瘤组织的浸润程度、转移程度和疾病的预后情况有密切关联。成为肿瘤靶向治疗的新靶点,尤其是在对抗血管生成疗法如抗VEGF-A和抗VEGF-2R受体治疗耐药的肿瘤治疗方面。因此对于DLL4在恶性肿瘤中的过度表达已成为近几年来的研究热点之一。